The predominance of research on heterotypic immunity to influenza infection has focused on T cell responses in the lungs. However in man, influenza normally first infects the nasal mucosa, and then spreads progressively to the trachea and to the pulmonary airways. Thus, to rationally develop an effective vaccine to influenza, it will be necessary to understand immune responses to influenza in both the upper and lower respiratory tract. In fact, we would argue that most effective influenza vaccine would induce immunity that would stop an influenza infection at the upper airways before it could spread to the lung. The goal of this proposed research is to better understand how different subsets of CD4 and CD8 T cells, contribute to resistance to influenza infection in the upper respiratory tract. We hypothesize that the host primary and recall T cell responses of the nasal mucosa are under local control and have little effect on responses in the lung. However, we believe those T cell responses to influenza in the lung and associated lymphoid tissues determine responses not only in the lung, but also affect responses of the nasal mucosa. Furthermore, that heterotypic immunity to influenza is most effective at resisting challenge of virus deposited on the nasal mucosa and not deposited directly in the lower respiratory tract. To address these hypotheses, accomplishment of the following specific aims is proposed: 1, To characterize the primary and memory T cell responses to influenza infection in the mucosa of the nasal passages and trachea and compare these to the responses in the lower respiratory tract. 2, To characterize the roles of NALT and the cervical lymph nodes (CLN) in T cell responses to influenza in the upper respiratory tract and compares these to responses of the BALT and TBLN of the lower respiratory tract. 3, To determine how the initial deposition of virus at different levels of the respiratory tract affects primary and memory responses to influenza. We believe that it is important to understand immune responses to influenza at the initial site of infection so that immunotherapies can be rationally developed to take advantage of these mechanisms. This could result in protection that would avoid the damaging effects of infection and host response in the fragile and vital tissues of the lower respiratory tract.